DE2621906C2 - - Google Patents

Description

The invention relates to the use of a mixture of dihydroergotamine or a salt thereof and Etilefrin or a salt thereof in a proportion of the above Active ingredients from 1 to 10 for the manufacture of a drug for the treatment of orthostatic circulatory disorders, the Medicinal products to be produced are preferably an oral pharmaceutical form is.  

The mixture to be used according to the invention can be obtained by either (a) Dihydroergotamine or its salts with polyvinylpyrrolidone processed into a solid material and mixed with Etilefrin or its salts or (b) dihydroergotamine or its salts with etilefrin or mixed its salts.  

In the mixture to be used according to the invention the ratio of dihydroergotamine (in mg) to etilefrin (in mg) 1 to 10, both components in the form of their salts can be present.

The procedure given under a) can be done as described below:

Dihydroergotamine or its salts, where as salts expediently salts with harmless acids, such as methanesulfonates, maleinates or tartrates, used together with polyvinylpyrrolidone in the form of poly-N-vinylpyrrolidone-2 (uncrosslinked) with Molecular weights between 10,000 and 100,000, in particular 11,500 to 40,000, preferably 25,000, if appropriate along with pharmaceutically acceptable Additives, for example surfactants, such as Polyethylene glycol fatty acid esters, in particular Polyethylene glycol stearate, as well as stability-enhancing Additives such as acids, in particular Methanesulfonic acids, maleic acid or tartaric acid, to achieve a pH of about 4-5 mixed. In this mixture is the weight ratio of dihydroergotamine or its salts to the polyvinylpyrrolidone used and any additives from 1:99 to 30:70, preferably 5:95 to 15:85.  

The mixture is in a suitable solvent, for example a lower alcohol such as methanol or ethanol, at elevated temperature, in particular from 30 to 80 ° C, preferably from 40 to 70 ° C, dissolved. After complete dissolution (clear solution) the solvent at temperatures from 50 to 80 ° C, preferably from 40 to 70 ° C, initially under normal pressure and then evaporated in vacuo. Here it is possible that in the preparation of the solution only part of the polyvinylpyrrolidone or the rest Additives are used and the addition of the rest Polyvinylpyrrolidons or the other additives during evaporating the solution. After complete Evaporation of the solution gives a clear liquid which solidifies at room temperature (15-25 ° C). The residue becomes a fine in the usual way Grind powder and this in vacuo at about 30 ° C to post-dried to completely remove the solvent.

The dried product is either with the appropriate A lot of Etilefrin or its salts, like one Hydrochloride or sulfate, or with the appropriate Amount of granules from Etilefrin or its Salts such as a hydrochloride or sulfate, and the commonly used for granule production pharmaceutical excipients added.  

The procedure given in section b) can be as described below:

Dihydroergotamine or its salts are used together with Etilefrin or its salts in a manner known per se mixed. The mixing is advantageously carried out so that one or a dihydroergotamine methanesulfonate from this, if necessary with the help of the usual Excipients, granules produced on known Way mixed.

That by using the specified Mixture of dihydroergotamine or its salts and of Etilefrin or its salts according to the invention are characterized by a potentiated increase in tone in the capacity vessels out. The through the synergism of both active ingredients achieved increase in volume elasticity coefficient E ′ (see M. Echt and L. Lange in "The Orthostatic Syndrome", 5th Rothenburg conversation, page 111, F. K. Schattauer Verlag) is on average more than 500%. Such Tonus enhancement is not in itself with either of the two pharmaceuticals to reach.

Because of this beneficial effect, this combination is particularly suitable for the treatment of orthostatic circulatory disorders.  

Favorable effects in the correction of orthostatic Circulatory disorders are obtained with daily oral administration of the mixture of 0.5 to 5 mg dihydroergotamine and from 5 to 50 mg Etilefrin, with both components in salt form can. A mixture of is particularly preferred 2 mg dihydroergotamine methanesulfonate and 20 mg etilefrin hydrochloride, to be administered twice a day.

Examples of oral dosage forms, which are can be made using the invention Tablets, hard gelatin capsules, soft gelatin capsules and Coated tablets. These dosage forms are used known additives of organic or inorganic auxiliaries and for example binders (such as gelatin, Polyvinylpyrrolidone), lubricants (such as stearic acid, magnesium stearate, Talc), fillers (such as lactose, calcium carbonate), Disintegrants (such as starches, alginic acids), if necessary still flavors and colors on per se known Manufactured way.

A preferably tablet combination of 180 mg target weight consists of

Etilefrin 20.0 dihydroergotamine methanesulfonate 2.0 silica 0.9 gelatin 1.0 corn starch 11.3 polyvinylpyrrolidone 11.3 talc 14.9 cellulose powder 26.9 milk sugar 89.7 180.0

example Mixtures for oral administration Procedure 1 a) preparation from dihydroergotamine methanesulfonate and Polyvinyl pyrrolidone

34.6 g of dihydroergotamine methanesulfonate, 195.4 g polyvinylpyrrolidone (average mol. wt. 25,000) and 500 ml of methanol. The flask is connected to a rotary evaporator. At a bath temperature of 60 ° C with rotating Flask the contents heated to approx. 60 ° C. This creates a clear solution.

From the solution under reduced pressure (approx. 250 torr) and a bath temperature of 60 ° C. distilled off as much methanol, until the residue has a syrupy consistency has reached. This mass is placed in an evaporating dish brought and about 2 hours at room temperature kept. Then drying (vacuum drying cabinet, 30 ° C, approx. 1 torr, approx. 12 hours), grinding and drying.

b) Etilefrin hydrochloride granules

346.0 g of etilefrin hydrochloride are placed in a planetary mixer with 650.9 g milk sugar and 110.4 g corn starch mixed. This mixture is mixed with a solution of 17.3 g Gelatin moistened evenly in 70 g water, through  a sieve with a mesh size of 1.3 mm granulated and Drying cabinet dried at 50 ° C for 12 hours. The dried granulate is passed through a sieve with a mesh size Sieved 1.0 mm.

c) mixture

230 g of the preparation prepared according to a) and 1124.5 g of the granules produced according to b) are in a free-fall mixer together with 895.0 g milk sugar, 86.5 g corn starch, 467.0 g of cellulose powder, 294.0 g of talc and 17.0 g Silicic acid mixed until homogeneous distribution. The mixture is made with the usual pharmaceutical Presses processed into tablets of 180 g nominal weight.

Procedure 2

1124.5 g of the granules produced by process 1b) are mixed in a mixer with 34.6 g of dihydroergotamine methanesulfonate, 895.0 g milk sugar, 86.5 g corn starch, 662.4 g Cellulose powder, 294.0 g talc and 17.0 g silica mixed until homogeneous distribution. The mixture prepared in this way is mixed with the usual ones pharmaceutical presses to tablets of 180 g nominal weight processed.

Claims (2)

1. Use a mixture of dihydroergotamine or one Salt thereof and Etilefrin or a salt thereof in one Quantity ratio of the mentioned active ingredients from 1 to 10 for the production a medicine for the treatment of orthostatic Circulatory disorders. 2. Use according to claim 1, characterized in that the drug to be manufactured is an oral drug form.